The vascular endothelium is the innermost layer of cells in the blood vessels, located at the interface between the blood and the vessel wall. The cells form a slick layer that prevents blood cell interaction with the vessel wall as blood moves through the vessel lumen. The endothelium plays a critical role in the mechanics of blood flow, the regulation of coagulation, leukocyte adhesion, and vascular smooth muscle cell growth, and also serves as a barrier to the trans-vascular diffusion of liquids and solutes. The endothelium performs many active functions, such as the secretion and modification of vasoactive substances and the contraction and relaxation of vascular smooth muscles.
Endothelial dysfunction is believed to be an important factor in the development of atherosclerosis, hypertension and heart failure. Furthermore, endothelial dysfunction is believed to be an effective predictor of cardiovascular diseases before the disease becomes symptomatic. Hence, there is a high interest in the assessment of the endothelial function in subjects under risk of potential cardiovascular diseases. Publications from recent years show that the endothelial function (or rather, lack thereof) of peripheral arteries is a good predictor for the coronary arterial system.
Some of the publications on the subject are: Volker Schächinger et. al, Circulation. 2000;101:1899-1906; Amudha Kadirvelu, et. al, Medical Progress May 2002; 4-12.; Eva Sondergaard et. al, Am Heart J 144(1): 2002,108-114, the disclosures of which are incorporated herein by reference.
A known method for assessing the endothelial dysfunction of peripheral arteries is described, for example, in Mary C. Corretti et. al. J Am Coll Cardiol 2002; 39:257-265, the disclosure of which is incorporated herein by reference. The method includes measurement of a baseline brachial artery diameter using an imaging apparatus (e.g., ultrasound), stimulation of the endothelium to release the vasorelaxing factor nitric oxide (NO), re-measurement of the artery diameter after the stimulation and computation of the change in the arterial diameter. The release of NO results in relaxation of the smooth muscles cells and increases the radius of the blood vessels.
The endothelial function (or dysfunction) is assessed from the relative increase (in %) of the brachial artery diameter relative to baseline due to the stimulation. A typical diameter change for healthy subjects with proper endothelial function is of the order of 7% whereas for subjects with endothelial dysfunction, the diameter change is substantially lower. Other diagnostic indices used relate to the timing of the peak change, rate of return to baseline and area under the relative change.
This test method is hard to implement, due to the difficulty to accurately measure the diameter of the artery using imaging methods and a high skill required from an operator carrying out the method in positioning the apparatus used for the imaging. In practice, although the test is widely recognized as important, it is not widely used.
U.S. Pat. No. 6,152,881 to Rains et. al., the disclosure of which is incorporated herein by reference, describes a method of assessment of endothelial dysfunction, in which the changes in artery volume are determined from changes in the internal artery pressure, as measured by a pressure measurement cuff. The pressure measurement cuff is used to sense the internal artery pressure. The cuff is suggested to be held during the measurement at diastole or near diastole pressure, so that the pressure changes in the cuff reflect the changes in the artery, due to the cardiac cycle. According to the suggested method, NO release is induced by occlusion of the artery for a few minutes and then the pressure in the cuff is monitored for about ten minutes until the artery returns to its normal state. The resultant pressure graph is analyzed to determine the endothelial functioning of the patient. The method of U.S. Pat. No. 6,152,881 requires that the patient remain relatively still for a long period (i.e., about ten minutes).
The method of the U.S. Pat. No. 6,152,881 patent applies pressure to the patient continuously for a relatively long time period, in which return blood flow through the veins is hampered, possibly affecting the measurement results. In addition, if the blood pressure of the patient changes during the measurement, wrong results may be received. In addition, the accuracy of the method is relatively low because it monitors relatively small modulation in the artery diameter.